Most radiosensitizing agents that are useful in the treatment of cancer have been identified from empiric laboratory or clinical observations, without adequate knowledge of the molecular basis of interaction of these agents. Efforts to enhance the efficacy of radiation are based on exploitation of the mechanisms of radiation effect and resistance. The six general mechanisms are as follows: hypoxic sensitization, enhancement of DNA injury, decreased DNA repair, increased apoptotic cell death resulting from DNA injury, effects on tumor vasculature, and cell-cycle effects (Nature Clinical Practice Oncology, 2007, 4(5), 282-294). For decades, investigations focused on the problem of tumor hypoxia as a cause of radiation resistance (British Journal of Cancer, 2000, 83(3), 354-359). Hypoxic cells are resistant to radiation in vitro and in vivo. Early experiments indicated that a modest amount of oxygen was required for DNA injury at the moment that radiation was administered; but that once a threshold level of oxygen was present (e.g. as in normal tissues) giving more oxygen would not further enhance the radiation effect. Oxygen is necessary for free-radical-mediated radiation induced DNA injury. It was proposed that resistant hypoxic-cell populations could be a major cause of treatment failure and this could be overcome by enhancing oxygen delivery or administering drugs that act like molecular oxygen. Drugs that preferentially kill hypoxic tumor cells, such as mitomycin and tirapazamine, show potential benefit and are under study.
Despite the importance of the phenomenon of hypoxia, efforts addressing tumor hypoxia have not been successful. Several potential reasons for this failure include toxicity of the agents, which limits dosing, self-correction of hypoxia that occurs during fractionated radiotherapy, whereby the death of normoxic cells allows oxygen to reach formerly hypoxic cells, hypoxia-mediated upregulation of resistance genes, and the fact that the existence of hypoxia is a marker for a resistant tumor rather than the cause of aggressiveness (Nature Clinical Practice Oncology, 2007, 4(5), 282-294).
The limited success at overcoming hypoxia has led to other approaches being developed to enhance radiation efficacy. The most studied and clinically successful approach for combating tumor hypoxia is the administration of cytotoxic chemotherapy concomitantly with radiation. The mechanisms that result in improved outcome with this combination include the following: simple independent additive effects on cell killing; arrest of cells in a radio sensitive portion of the cell cycle (e.g. G2-M); targeting of resistant populations such as hypoxic cells or those in resistant parts of the cell cycle; and enhancing radiation-induced DNA injury or preventing its repair. Additionally, a tumor can proliferate in due course of radiation with a rate of growth that could counteract much of the cytotoxic effect of radiation. This proliferation is termed accelerated repopulation, and can occur as a result of improved nutrients and blood supply to surviving cells or a remaining population of radiation-resistant cells. This proliferative response may be overcome by using a cytotoxic agent in addition to radiation. Chemotherapy has been combined with radiotherapy in an effort to optimize the therapeutic index of radiotherapy in treatment of cancer. It is desirable to develop radiosenstitizers that augment the efficacy of radiation therapy for cancer, thus allowing a lower radiation dose, potential target specificity and clinically acceptable toxicity.
PCT Patent Publication No. WO2004004632 (corresponding to U.S. Pat. No. 7,272,193) and PCT Patent Publication No. WO2007148158 describe pyrrolidine substituted flavones as CDK inhibitors with utility in the treatment of different types of cancers. CDK inhibitors are less toxic and hence it would be advantageous to evaluate the effect and possible mechanism of CDK inhibitors on enhancing the radiosensitivity in human cancer. This would be highly beneficial to cancer treatment through radiation.